Int. J. Pharm. Sci. Rev. Res., 25(1), Mar – Apr 2014; Article No. 29, Pages: 171-177 ISSN 0976 – 044X
Sukrutha S.K, Savitha Janakiraman*
Department of Microbiology and Biotechnology, Jnanabharathi Campus, Bangalore University, Bangalore- 560056, Karnataka, India
*Corresponding author E-mail: drsvtj@yahoo.co.in
Accepted on: 31-12-2013; Finalized on: 28-02-2014.
ABSTRACT
Consumption of fish/fish oil has been reported to modulate the symptoms in cardiovascular disease, inflammatory responses, cancer, and neurological disorders. The objective of this review is to provide therapeutic role of polyunsaturated fatty acids (PUFA) with practical evidences carried out in recent years. Literature studies were selected using the Google, Pub Med and Medline database on the basis of the following criteria: (1) significance of omega-3-fatty acid in nutrition and disease (2) randomized controlled design, placebo controlled studies using Eicosapentaenoic acid and Docosahexaenoic acid. Imbalance in fatty acid composition is thought to be the major risk factor for the development and progression of various diseases. Omega-3 fatty acid up regulates anti-inflammatory and antiapoptotic gene expression. It also competes with enzymes essential for ω -6 PUFA derived proinflammatory eicosanoid mediators. In addition, it reduces blood pressure, angiogenesis process. Interactions of PUFA with signal transduction pathways reverse the symptoms associated with depression whereas transcription factors modulates tumor metabolism. Consumption of fatty fish/ fish oil is associated with reduced risk for cardiovascular disease, inflammatory responses, cancer and neurological disorders.
Keywords: ω -3 polyunsaturated fatty acids, Eicosapentaenoic acid, Docosahexaenoic acid, biopharmaceuticals, health disorder.
INTRODUCTION
F atty acids are chains of hydrocarbons with carboxylic acid (COOH) at one end and an methyl group system cannot place a double bond at the third carbon at the other end. Human and mammalian position or in the sixth carbon position from the methyl end or omega end of the fatty acid (FA) chain. For this reason, linoleic acid (LA, 18:2) and alpha- linolenic acid
(ALA, 18:3) are called as essential fatty acids (EFA).
Polyunsaturated fatty acids (PUFAs) include the family of
ω 3 and ω -6 fatty acids. Omega-3 series are derived from
ALA and omega-6 from linoleic acid. Alpha-linolenic acid is converted into long chain ω -3 PUFA such as
Eicosapentaeonic acid (EPA, 20:5, ω -3) and
Docosahexaenoic acid (DHA, 22:6, ω -3). Similarly, LA can be sequentially converted via biosynthetic pathway into other ω -6 fatty acids i.e Gamma-linolenic acid (GLA, 18:3,
ω−6), Arachidonic acid (AA, 20:4, ω−6) and Di -homogammalinolenic acid (DGLA, 20:3, ω -6). Since Burr and
Burr’s
1
dis covery of EFA namely ω 6 LA and ω -3 ALA, the subject on PUFAs has opened to a better understanding of their role in public health and disease [Figure 1]. those us ed to metabolize ω -6 PUFAs (elongases, ∆
5
and ∆
6 desaturases), ALA is converted to EPA (20:5, ω -3) by ∆
5 and ∆
6 desaturase. Eicosapentaenoic acid is the precursor of 3 series of PGs, 5 series of LT and resolvins. Since LA and ALA compete for the same set of enzymes abundant of one reduces the metabolism of the other. Under an ideal physiological ratio of 1:4, ∆
5
and ∆
6 desaturases and elongases have higher affinity to metabolize ω 3 over ω -6
PUFAs. Eicosapentaenoic acid further gets converted to
DHA by elongases and ∆
6 desaturase respectively. Only 8-
20% of ALA is converted into EPA in humans, ALA to DHA is less or around 0.5-9%. This lower rate of conversion is unlikely to provide sufficient levels of EPA and DHA for normal health and therefore mammalian system is dependent on dietary sources rich in polyunsaturated fatty acid. In recent years, tremendous work has been carried out worldwide to elucidate the therapeutic importance of PUFAs, in general, and omega-3-fatty acids, in particular, in human health care. This review gives compilation of theoretical and practical evidences published on this topic for the past five years for the benefit of scientific and unscientific society.
Although mammalian cells cannot synthesize LA and ALA they can be formed by the introduction of double bonds
(desaturation step) via ∆
5
and ∆
6 desaturase and by increasing the acyl chain (elongation) via elongases
[Figure2]. Consequently, LA is converted to GLA by the action of ∆
6 desaturase and GLA is elongated to form
DGLA, the precursor of the 1 series prostaglandins (PGs).
Dihomo-gamma-linolenic acid is further converted into
AA (20:4, ω -6) by ∆
6 desaturase. Arachidonic acid is the precursor of 2 series of PGs, thromboxanes, 4 series of
Leukotrienes (LT). Using the same series of enzymes as
Figure 1: Properties of omega-3-fatty acid
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Int. J. Pharm. Sci. Rev. Res., 25(1), Mar – Apr 2014; Article No. 29, Pages: 171-177 ISSN 0976 – 044X
Table 2
Vegetables Fat content and oils (g/100 g)
Eel
Hering
Sprat
Tuna
Salmon
Mackerel
Carp
Sardine
Swordfish
Trout
Halibut
Cod
Haddock
Lobster
Shrimp
Mussels
Anchovy
Sardine
24.5
17.8
16.6
15.5
13.6
11.9
4.8
4.5
4.4
2.7
1.7
0.6
0.6
1.9
1.4
1.4
2.3
13.9
1.39
1.79
0.59
0.51
0.18
0.16
0.2
0.3
EPA +
DHA (g/
100 g)
0.83
2.72
3.23
3.37
2.86
1.75
0.3
0.15
0.5
2.44
Fat content (EPA
+ DHA) EPA +
DHA (g 100 g)
29.51
6.54
5.14
4.6
4.76
6.8
16
3.24*
2.45*
4.58
3.33*
3.33*
3.75*
9.5
4.66
9.33
4.6
5.7
Figure 2: Biosynthetic pathway of polyunsaturated fatty acid and their mediators
SOURCES OF PUFA
Seaweeds and unicellular phytoplankton are the major sources of ω -3 FA (EPA & DHA). Marine fishes are enriched with long chain PUFA (LC-PUFA) as they consume phytoplankton and get transferred to different levels of species through food chain
2
(table 1). Cold water oily fishes such as salmon, herring, mackerel and sardines are also rich in EPA & DHA. Oil from red and brown algae is a good source of ω -3 PUFA all PUFAs essential for infant growth
ALA are present in significant amounts in vegetable oils and in other natural sources
5
3
. Breast milk comprises of
4
. Linoleic acid and
(table 2 and table 3).
Table 1
Fish ⁄ sea food
Fresh tuna
Sardines
Salmon
Mackerel
Herring
Rainbow trout
Halibut
Gram to provide 1g EPA and DHA per day
70–360
60–90
60–135
60–250
45–60
90–105
90–225
Cod
Haddock
Catfish
375–750
450
Flounder
Oyster (Pacific ⁄ eastern ⁄ farmed)
Lobster
75
450–600
210
⁄ 195 ⁄ 240
Crab, Alaska King
Shrimp
Clam
225
255
330
375
Scallop 525
Amounts (g) of few sea fish foods which should be consumed to provide
1 g EPA and DHA; Source: Ward & Singh (2005)
Table 3
Fat content ALA (g
(g 100g) 100g)
Butter
Lard
Linseed oil
Soybean oil
Rapseed oil
Walnut oil
Olive oil
Vegetable oil
Almonds
Hazelnut
Walnuts
Kale
Lettuce
Parsley
Potato
Cauliflower
Spinach
White cabbage
Wheat bran
100
100
80
54.1
61.6
62.5
0.9
0.22
0.36
83.2
100
100
100
100
0.11
0.18
0.3
0.2
4.65
Fat content
⁄ ALA (g
100g)
1.2
0.98
54.2
7.7
9.15
13.5
0.86
2.4
0.26
0.15
6.8
0.35
0.07
0.12
0.02
0.1
0.13
0.09
0.16
Fat content
(g 100g)
69.3
102.04
1.84
12.98
10.93
7.40*
6.25
33.3
208.07
410.6
9.19
2.57*
3.14*
3*
5.5*
1.8*
2.31*
2.22*
29.06
Fat content ⁄ EPA + DHA (g 100 g) and fat content ⁄ ALA (g 100 g) ra o of some various fish, marine products, vegetables and oils; Source: Sauci et al (1994)
*Food which appears as perfect from the point of omega 3 content
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Int. J. Pharm. Sci. Rev. Res., 25(1), Mar – Apr 2014; Article No. 29, Pages: 171-177 ISSN 0976 – 044X
OMEGA FATTY ACIDS AND NEUROLOGICAL DISORDERS
There appears to be sufficient evidences on the importance of PUFAs in brain function. A preponderance of this research has focused on DHA, that is preferentially deposited in brain phospholipids and has been linked to
Dementia, Parkinson disease, Alzheimer disease (AD),
Huntington’s Disease, Cognition, Suicide, Depression,
Bipolar disorders, Schizophrenia and Mood disorders,
Anxiety, Aggression
6-16
etc.
Depression and Mental Disorders
Interestingly, ω -3 PUFA has been reported to be effective against depressive disorders. Imbalance in FA composition is the leading cause of mood disorders.
Docosahexaenoic acid helps in the maintenance of neuronal membrane stability and regulates the function of serotonin and dopamine transmission, the key components for depression. and DHA in particular has emerged as a potential tool against Alzheimer’s disease.
Docosatriens (10, 17s) also known as Neuroprotectin D1
(NPD1) are conjugated triene structures derived from
DHA (Figure 3). They possess immune-regulatory and neuroprotective properties
8
. Addition of nano molar concentration of DHA to primary co-cultures of human neurons and glial cells have resulted in 20-25% decrease in amyloid β (aβ) production, accompanied with NPD1 biosynthesis and 5 0% decrease in apoptosis caused by aβ.
This neuroprotective property is due to upregulation of anti-inflammatory and anti-apoptotic genes namely antiapoptotic Bcl-2 & Bcl- XL
29
.
In a double blind (DB) intervention study, supplementation of 2.5g/day of ω -3 PUFA for two months significantly reduced depressive symptoms among elderly patients suffering from major depression/dysthymia and resulted in significant decrease in AA/EPA ratio in red blood cells membrane and improved phospholipid FA profile
17
. In a nine week randomized, masked, placebocontrolled [PC] study, combination therapy (2gms containing a blend of 900mg EPA, 200mg DHA, and
100mg other ω -3 fatty acids twice daily plus citalopram (a selective serotonin uptake inhibitor) displayed significant improvement in ameliorating signs and symptoms of major depression disorder in forty two subjects than monotherapy (2 grams olive oil per day plus citalopram)
18
. Evidences from randomized, DB, PC study suggests that compared to placebo, supplementation/diet enriched with ω -3 PUFA may protect elderly patients with mild cognitive impairment from cognitive decline and ameliorate depressive symptoms and the risk of progressing to dementia
19-21
. Supplementation of EPA ≥
60% of total EPA + DHA (200-2200 mg/d) was effective against primary depression
22
.
Figure 3: Neuroprotectin D1 biosynthesis and its function
Increased suicide risk is associated with lower intake of
PUFA in Japanese women compared to men proportion of ω -
.
6/ ω
23
. Lower levels of PUFA concentrations (DHA and AA) are seen in erythrocyte membranes of schizophrenia patients
24
. In a two DB, PC pilot studies on schizophrenia patients, EPA treatment benefited persons suffering from schizophrenia compared to DHA
25
. Supplementation of 1g/day of ω -3
PUFA showed positive effect on the patients suffering from persistent depression
26
. According to a case study,
-3 ratio, plasma DHA, HDL is associated with mental retardation in mentally retarded children in Korea
27
Alzheimer disease
Studies suggest that, apolipoprotein-E polymorphism is the major genetic risk factor for the development of sporadic Alzheimer’s disease
28
. Several epidemiological studies and clinical tri als suggest that ω -3 PUFA in general
In a randomized DB, PC OmegAD study, dietary administration with either 1.7 g of DHA and 0.6 g EPA or placebo for 6 months to 174 AD patients resulted in downregulation of genes involved in inflammation regulation, neurodegeneration and significantly improved plasma EPA & DHA levels
30
.Evidences from randomized,
DB, PC study suggests that compared to placebo, supplementation/diet enriched with ω -3 PUFA may protect elderly patients with mild cognitive impairment from cognitive decline and ameliorate depressive symptoms and the risk of progressing to dementia.
However, supplementation of LC-PUFA showed no benefit on cognitive function in cognitively healthy older people and in patients with mild to moderate Alzheimer disease
31- 33
. Addition of 5-20 µM DHA inhibits A β fibrillation under in vitro and in vivo conditions. This function attributes to anti-amyloid properties of docosahexaenoic acid. Overall these results suggest that
DHA & EPA may be used as a potential therapeutic agent against mild cognitive impairment and ALZ disease
34-36
.
Conversely, compared to placebo, supplementation of algal DHA (2g/d) for 18 months did not slow the rate of cognitive and functional decline in patients with mild to moderate Alzheimer disease
37
.
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Int. J. Pharm. Sci. Rev. Res., 25(1), Mar – Apr 2014; Article No. 29, Pages: 171-177 ISSN 0976 – 044X
OMEGA-3 FATTY ACIDS AND CARDIOVASCULAR
DISEASES (CVD)
Cardiovascular disease is a leading cause of mortality and morbidity worldwide today. Decreased risk of CVD was observed in Greenland Eskimos who consumed fish enriched with ω -3 fatty acids
38, 39
. According to the World
Health Organization recommendations, the optimal ratio of ω 6 to ω -3 PUFAs is 5-8:1. At this ratio, consumption of
LC-PUFA in food or in the form of drugs can act as potent antagonists to ω -6 PUFA synthesis and acts as membrane protectors, inhibiting the synthesis of AA from linoleic acid and competing with AA for the binding to cell membrane phospholipids
40, 41
.
Cardiovascular protective nature of LC-PUFA is attributed to its property of reducing cholesterol and thus the risk of myocardial infarcation (MI), serum triglyceride in blood serum level of hyperglycemia patients, decreasing plasma triacylglyceride, blood pressure, platelet aggregation, inflammation, easing blood circulation
42-48
. Supporting evidences followed by expanded interest on omega-3index indicates that persons having omega-3-index <4% are at a tenfold higher risk to CVD than individuals with an omega-3-index >8%
49
. In a case control study, intake of
ω -3 PUFA significantly decreased plasma lipid hydroperoxide level and thereby reduced the level of oxidative damage among elderly patients with MCI
50
.
Addition of EPA and DHA (50300µM) helps in down regulating cholesterol absorption genes such as NPC1L1 and its protein expression in human enterocytes in vitro
51
. Supplementation of ω -3 PUFA showed beneficial effects in the prevention of atrial fibrillation recurrence
52,
53
. Conversely, in a randomized, DB, multicentre study, treatment with PUFA did not reduce recurrent atrial fibrillation
54, 55
.Treatment with DHA (200mg/kg) attenuated the expression of TNFα -induced vascular cell adhesion molecule 1 (VCAM-1) and NFκB activation in
TNFα -treated human aortic endothelial and thereby contributing to the prevention of atherosclerosis in mice
56
.
OMEGA -3 FATTY ACIDS AND CELL PROLIFERATION
Ecological studies have shown that high per capita fish consumption is correlated with a lower incidence of cancer in the population
57
. Indeed, epidemiological studies suggest that Eskimos and Alaskans who consume large quantities of fish have a low risk for cancer
58
.
Several molecular mechanisms whereby ω -3 PUFA potentially inhibits carcinogenesis have been proposed
59
.
These mechanisms include
1) Inhibition of eicosanoids derived AA
2) Modulation of transcription factor, gene expression and signal transduction which leads to changes in tumor metabolism, proliferation and differentiation
3) Changes in estrogen metabolism
4) Decreasing the levels of free radicals and reactive oxygen species
5) Expression of apoptotic inducing B ax
, p53 proteins
6) Reduction in angiogenesis process
Prostate cancer is the most commonly diagnosed cancer and is one of the leading cause of death among men in
America
60
. Addition of ALA/DHA to gastric epithelial cells inhibited oxidative stress induced cellular events such as glucose oxidase mediated apoptosis, DNA fragmentation, induction of p53 and B ax proteins
61
.Omega-3-fattyacids post-transcriptionally regulates over expression of Zeste
Homologue2 (EZH2), a polycomb group protein in breast cancer cells
62
.Recently EPA has shown to be beneficial in anti-cachexia therapy
63
. In a prospective cohort study on
Shanghai women fed with diet lower in ω -3 PUFA suggest that, two fold increase in breast cancer risk in women compared to subject s consuming diets enriched with ω -3
PUFA
64
. Intake of ω -3 PUFA from fish has inverse relation with postmenopausal breast cancer risk
65
.
Recent studies reports that, LC-PUFA may be used as a therapeutic agent for the chemoprevention of human pancreatic cancer
66, 67
. Increase intake of food and supplements rich in PUFA is associated with reduced risk of endometrial cancer
68
. Docosahexaenoic acid inhibits the process of tumor establishment
69
. Furthermore, ω -3
PUFA has shown to reduce angiogenesis, decreases nuclear factor– κβ (NF κβ) activation
70-72
. Increasing body of evidence has shown that, supplementation of DHA upregulates syndecan-1 (SDC-1, a tumor suppressor molecule), which induces apoptosis through activation of
PPARγ and inhibits MEK/Erk/Bad signaling under in vitro and in vivo conditions
73, 74
.
OMEGA-3 FATTY ACIDS AND RHEUMATOID ARTHRITIS
Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic inflammation of the joints. In vitro study test on various PUFAs showed that ω 3 PUFAs not ω -6
PUFAs are able to markedly decrease mRNA expression level of key initial cartilage degrading proteinases
(ADAMTS-4& -5) and Cox-2 and also reduced the levels of inflammatory cytokines, TNFα, IL 1α and IL 1β
75
.
Molecular mechanism by which ω -3 PUFAs may help to reduce the symptoms of RA are as follows
76
:
1.
Compete with enzymes essential for ω -6 PUFA derived pro-inflammatory eicosanoid mediators
2.
Reduce the gene expression of Cox-2 enzyme, cytokines, TNFα, IL 1α, IL 1β
3.
Reduce the gene expression of key initial cartilage degrading proteinases such as ADAMTS-4 and -5, matrix metalloproteinases -3 and -13
The above supporting evidences indicate that, supplementation of EPA helps in the reduction of proinflammatory agents which plays a key orchestral role in causing inflammation in rheumatoid arthritis.
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CONCLUSION
Polyunsaturated fatty acids are the precursors to a variety of potential mediators with diverse biological function.
However, molecular mechanisms behind these specific biologically active molecules in various cells and tissues processes still remain unclear. Furthermore, when these fatty acids are incorporated into the cell membrane they tend to alter its properties including composition of fatty acids, fluidity, that in turn helps in the modulation of the number and affinity of various receptors, ligands to their respective growth factors, co-factors, enzymes, hormones, peptides and proteins. Yet another action is their ability to form complexes with other biologically active molecules such as aspirin. Formation of such complexes between PUFAs and other biologically active molecules could help in the synthesis of newly formed derivatives like NPD1 that in turn shows varied biological actions useful to our body. Elucidating the role of enzymes in the pathway, formation of such biologically active complexes is not only interesting but also challenging since such complexes may form the basis of understanding certain less well understood physiological and pathological processes. Furthermore, studies have to be carried out on pro and anticancer, anti-inflammatory association of ω -3 fatty acids. Synthesis of synthetic and stable potent eicosanoids such as LXs, resolvins, and
NPD1 would help in amelioration of several inflammatory responses. In view of their diverse actions, PUFAs may lay a strong foundation for the formulation of many pharmaceutical drugs.
Acknowledgement: The authors acknowledge University
Grant Council (UGC), India, for funding research project entitled “Lipid profile of endophytic fungi: Identification of suitable strain for the production of commercially important omega fatty acids (EPA & DHA)”.
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Corresponding Author’s Biography: Dr. J. Savitha
J. Savitha received her Ph.D. degree in Botany, Madras University and postdoctoral research in
University of Hull, England under the Jawaharlal Nehru (UK) fellowship. She worked on the regulation of polyunsaturated acid (PUFAs) production in fungi under Prof. Colin Ratledge.
Currently she is working as an Associate Professor in Bangalore University, Department of
Microbiology. She is the Chairman of Board of Examinations (BOE) and member of Board of syllabus and Academic Council of Bangalore University. She has published 21 research papers and has several research projects offered by Government funding agencies. Her interest of research is on Industrial Microbiology and Environmental Microbiology.
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